Invasive interventions for brain disorders, such as tumors, functional problems, vascular malformations etc. are difficult and often disturb surrounding brain tissue and result in complications and long recovery times. In addition, the delivery of therapeutic agents via the blood supply is often impossible because the blood brain barrier protects the brain tissue from foreign molecules. Laboratory experiments have shown that focused ultrasound beams can noninvasively destroy deep tissue, close blood vessels, activate drugs, open the blood brain barrier, and perhaps increase the cell membrane permeability to molecules. However, the utilization of ultrasound in the brain has been seriously limited by the commonly accepted view that this technique requires the removal of a piece of the skull bone to allow the ultrasound beam to propagate into the brain. As a result, the therapeutic effects of ultrasound in the brain have not been widely explored in clinical trials. The hypothesis of this grant has been that transcranial therapeutic ultrasound exposures can be delivered without such surgery. During our current grant we have demonstrated that highly focused therapeutic ultrasound beams can be accurately delivered through an intact human skull noninvasively. Our results show that the ultrasound delivery can be done using phased array applicators that compensate for the wave propagation distortions introduced by thickness and density variations in the skull. Furthermore, we demonstrated using ex vivo human skulls that we can use CT-derived information to predict the phase shifts required for correcting the wave distortion. We have also developed a method to selectively open the blood brain barrier (BBB) without damaging the neurons in the targeted tissue volume. Similarly, we were the first to observe that apoptosis can be induced by ultrasound exposures in the brain. These two biological endpoints extend the therapeutic possibilities of this technique. Our study plan is to extend and build on our current research: First, to investigate the sonication parameters that produce different physiologic or histologic end points in the brain through in vivo rabbit and rat glioma studies. Second, to theoretically and experimentally optimize the phased array design and the energy delivery. Third, improve our theoretical treatment planning programs by taking into account all of the available information available from modern imaging systems and to test and improve these models in experiments with ex vivo human skulls. Finally, to integrate a complete phased array system, planning software, and sonication parameters from the animal experiments, and perform tests in preparation for human studies. Successful transcranial delivery of ultrasound will have a major impact on the treatment of brain disorders. Disorders targeted by existing surgeries will be treated in a fashion that is much less invasive, and completely new therapies may become available. A successful implementation of even one of the possible ultrasound therapies in the brain to routine cIinical practice would have a maior impact on patient care.